Pemphigus vulgaris (PV) is a potentially fatal blistering disease characterized by autoantibodies against cell surface adhesion proteins desmoglein (Dsg) 3 and Dsg1. Previous studies using phage display to clone Dsg-reactive monoclonal antibodies from a PV patient demonstrated that a limited number of antibody variable region genes encode the autoantibody repertoire, with different genes for pathogenic and non-pathogenic mAbs. Here, we investigated the feasibility of specific autoantibody targeting in pemphigus. We produced rabbit anti-idiotypic antibodies against two pathogenic and two non-pathogenic PV mAbs. Antisera inhibited binding of the immunizing mAb to Dsgs by ELISA as well as pathogenicity against cultured human keratinocytes. Antisera also inhibited other mAbs using the same variable region heavy chain (V_H) genes, despite different light chains or somatic mutations. Additionally, peptide phage display identified peptide sequences that bound PV mAbs in a V_H-specific manner. To evaluate the therapeutic potential of V_H gene-targeted reagents, preimmune sera and antisera were used to adsorb pathogenic antibodies from PV sera. Pooled antisera significantly reduced pathogenic activity from the original PV patient's serum and bound pathogenic antibodies from two other PV sera, suggesting shared autoantibody V_H gene usage among PV patients. Together, these data suggest novel V_H gene-targeted approaches toward PV treatment.